Total Synthesis of the Bacterial Diisonitrile Chalkophore SF2768

Article abstract of DOI:10.1021/acs.orglett.9b03348

Chalkophores are bacterial natural products that chelate and transport extracellular copper. The diisonitrile natural product SF2768 was first isolated from a Streptomyces species as an antifungal antibiotic and has more recently been characterized as a bacterial chalkophore and potential virulence factor. Herein, we report a modular synthesis of SF2768 and related acyclic analogues, allowing assignment of syn-stereochemistry across the central lactol ring. The copper-binding properties of these diisonitriles have also been studied.

Full text of DOI:10.1021/acs.orglett.9b03348

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Total Synthesis of the Bacterial Diisonitrile Chalkophore SF2768
Yao Xu† and Derek S. Tan*,†,‡
‡
†Chemical Biology Program, Sloan Kettering Institute and Tri-Institutional Research Program, Memorial Sloan Kettering Cancer
Center, New York, New York 10065, United States
S
* Supporting Information
ABSTRACT: Chalkophores are bacterial natural products that chelate and transport
extracellular copper. The diisonitrile natural product SF2768 was first isolated from a
Streptomyces species as an antifungal antibiotic and has more recently been characterized as
a bacterial chalkophore and potential virulence factor. Herein, we report a modular
synthesis of SF2768 and related acyclic analogues, allowing assignment of syn-
stereochemistry across the central lactol ring. The copper-binding properties of these
diisonitriles have also been studied.
opper is an essential element that is used as a cofactor for
a variety of enzymes that are important for cell growth
SF2768 was originally isolated from Streptomyces sp. SF2768
as an antibacterial and antifungal natural product.11 Sub-
sequently, SF2768 was identified as a cryptic antibiotic whose
production in a S. griseorubiginosus strain was triggered by
monensin.12 The related acyclic, ornithine-based natural
product SF2369 (2) had also been identified earlier as an
antifungal from Actinomadura sp. SF2369.13 Notably, two
lysine-based congeners (3, 4) have been identified recently by
Zhang and co-workers via heterologous expression of a
biosynthetic gene cluster from S. coeruleorubidus having
homology to a cryptic virulence factor gene cluster in
Mycobacterium tuberculosis.14,15 Related diisonitriles with
longer side chains (not shown) were also produced by
heterologous expression of the homologous gene cluster from
M. marinum. Interestingly, He and co-workers found that the
corresponding copper complexes of 3 and 4 did not
significantly increase intracellular copper concentrations in S.
thioluteus.10 Moreover, Zhang and co-workers showed that
deletion of the entire biosynthetic gene cluster in M. marinum
decreased the intracellular concentration of Zn but not Cu.14
Thus, it remains to be determined if these diisonitriles are
generally involved in the regulation of Cu or other metals as
well. To enable further chemical, structural, and biological
studies, we report herein a modular synthesis of SF2768 and
linear congeners 3 and 4. This work establishes the absolute
and relative stereochemistry of the central lactol motif. We also
report preliminary studies of the Cu- and Zn-binding
properties of these diisonitriles.
C
and survival.1,2 Conversely, excess copper can lead to cellular
damage due to the formation of reactive oxygen species.
Accordingly, copper homeostasis is highly regulated. Bacteria
use chalkophore natural products to chelate and transport
extracellular copper into the cell, and to sequester copper that
can be toxic at high concentrations due to formation of reactive
oxygen species.3−5 The best-studied chalkophores are mem-
bers of the methanobactin family, which are comprised of
ribosomally produced, post-translationally modified peptides6,7
that chelate copper in 1:1 stoichiometry using two hetero-
cycle−thioamide motifs. Recently, He and co-workers
identified the diisonitrile natural product SF2768 (1, Figure
1) as a new class of chalkophore that is structurally unrelated
Figure 1. Structures of diisonitrile natural products.
At the outset of our studies, the absolute and relative
stereochemistry of the central lactol moiety of SF2768 had not
been established. However, Zhang and co-workers had
determined that the NRPS adenylation domains from S.
coeruleorubidus and M. marinum were selective for L-lysine over
D-lysine, leading them to assign a 2L-configuration in linear
congeners 3 and 4.14 Thus, we presumed in our retrosynthetic
analysis that the central lactol motif of SF2768 is also derived
to the methanobactins and produced by a nonribosomal
peptide synthetase (NRPS8,9) pathway.10 SF2768 was
produced from an NRPS gene cluster from Streptomyces
thioluteus expressed heterologously in S. lividans. It was shown
to form copper complexes selectively when various metals were
included in the fermentation broth, to reduce Cu(II) to Cu(I)
upon binding, and to bind Cu(I) in 2:1 stoichiometry.
Treatment of wild-type S. thioluteus with Cu(SF2768)2 led to
an increased intracellular copper concentration. The relevance
of putative chalkophore transporters was also demonstrated in
the S. lividans model.
Received: September 21, 2019
© XXXX American Chemical Society
A
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from L-lysine (Figure 2). As the relative configuration at C5
was unknown, we pursued the synthesis of both diastereomers.
Figure 2. Retrosynthesis of SF2768. The approach assumes the lactol
is derived from L-lysine, by analogy to diisonitriles 3 and 4.
It should be noted that SF2768 was isolated as a mixture of α
and β anomers.11 Zhang and co-workers had also determined
an R-configuration for the β-isocyanobutyrate side chains of
linear analogue 4,14 and we assumed the same for SF2768, to
be derived from N-hydroxysuccinimide ester 5. We envisioned
that the central lactol motif 6 could be accessed from a
protected 5-hydroxylysine intermediate 7,16,17 which could be
synthesized via azido alcohol 8 as a mixture of syn and anti
diastereomers by epoxidation and ring opening of butenylgly-
cine precursor 9.18 The 2L-configuration would be set using
Williams’ diphenyloxazinone auxiliary-based method.19−21 We
envisioned that the linear diisonitriles 3 and 4 could be
synthesized analogously by acylation of a protected L-lysine
derivative (not shown) with NHS ester 5.
Figure 4. Synthesis of SF2768. The epimer (2L,5R)-1 was also
synthesized by the analogous route from (2L,5R)-8 (not shown).25
The (2L,5S) configuration was assigned by comparison to the 1H
NMR and 13C NMR spectra of the natural product.25
hydrogenolysis of the auxiliary.26 Thus, treatment of 8 with
TFA afforded oxazinone 13, which then underwent hydro-
genolysis−hydrogenation in MeOH to provide diamino ester
14 as its bis·TFA salt.27 Careful reaction monitoring minimized
formation of a caprolactam byproduct (∼20%). The crude
material was carried directly onto Boc protection to afford
isolable bis(Boc) diamino ester 7. Lactonization with PPTS
afforded 15.28 Initial attempts to acylate the corresponding
Boc-deprotected lactone resulted in caprolactam formation.
Thus, DIBAL reduction29 of 15 afforded lactol 16 as a mixture
of anomers. Finally, TFA deprotection generated the diamino
lactol intermediate 6, which underwent bisacylation with NHS
ester 5 to afford the syn-substituted diisonitrile (2L,5S)-1. The
lactol exhibited a 1.2:1 α/β ratio in DMSO-d6, but an inverted
1:1.2 α/β ratio in D2O. Overall, the synthesis provided the
diisonitrile in 7 steps (longest linear sequence) and 16.3% yield
from known azidoalcohol 8. We also synthesized the
corresponding anti diastereomer (2L,5R)-1 by the analogous
route from diastereomeric azidoalcohol (2L,5R)-8.25
Synthesis of the side-chain NHS ester 5 was readily achieved
in multigram quantities from R-3-aminobutyrate (10) by
formylation22 to formamide 11, activation to NHS-ester 12,
and conversion of the formamide to the isonitrile23,24 in 5
(Figure 3). The key δ-hydroxylysine derivative 8 was
Figure 3. Synthesis of NHS ester 5.
1
Comparison of the H NMR and 13C NMR spectra of the
synthetic syn-diastereomer (2L,5S)-1 and anti-diastereomer
(2L,5R)-1 to those reported for the natural product SF2768
isolated from Streptomyces sp. SF276811 and S. griseorubiginosus
strain 574,12 as well as from S. thioluteus via heterologous
production in S. lividans,10 clearly established the syn-
diastereomer as corresponding to the natural product stereo-
chemistry (Figure 5).25 The matching NMR spectra of
synthetic (2L,5S)-1 and the natural products also support
assignment of the L-configuration to the lysine-derived lactol,
synthesized essentially as previously described,18,25 as a
separable 1:1 diastereomeric mixture, providing convenient
access to both diastereomers at what would eventually be the
C5 position of SF2768.
Next, we investigated conversion of (2L,5S)-8 to the key
lactol intermediate 6 (Figure 4). Attempted direct hydro-
genation−hydrogenolysis of 8 led only to azide reduction. It
has been reported that removal of the Boc group facilitates
B
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1
Figure 5. Selected regions of H NMR (left) and 13C NMR spectra
(right) of natural product SF2768 (top),12 synthetic syn-diastereomer
(2L,5S)-1 (middle), and synthetic anti-diastereomer (2L,5R)-1
(bottom) in D2O.25
although the diastereomeric D-lysine-derived diisonitrile was
not synthesized for direct comparison.
We also synthesized the corresponding acyclic diisonitriles
by bisacylation of L-lysinol acetate30 with NHS ester 5 to
generate diisonitrile acetate 4 (i-Pr2NEt, THF, 82%), followed
by deacetylation to afford diisonitrile alcohol 3 (K2CO3,
MeOH, H2O, 90%).25 The 1H and 13C NMR spectra matched
those reported for the natural products produced by
heterologous expression.10,14,25
Figure 6. (a) Formation of 2:1 complex of diisonitrile acetate 4 with
Cu(I). (b) H NMR titration (DMSO-d6) of diisonitrile acetate 4
with varying amounts of Cu(I).
1
titration with disodium bathocuproinedisulfonic acid (BCS).
BCS is known to bind Cu(I) as a stable 2:1 complex
Cu(BCS)23−, with an overall two-step association constant of
β2 = 1019.8 M−2 (λmax = 483 nm, ε = 13300 M−1 cm−1).35
However, no formation of the Cu(BCS)2 complex was
observed (A483) when the Cu(I) complex of diisonitrile
acetate 4 (40 μM in 25 mM HEPES buffer) was treated with
up to a 100-fold excess of BCS (Figure 7a).25 Conversely,
We next investigated the copper-binding properties of these
diisonitriles. Previously, He and co-workers reported that
SF2768 binds Cu(I) and Cu(II) selectively over 14 other
metals, in 2:1 stoichiometry based on HR-ESI-MS-based
titration experiments.10 Notably, the MS results indicate that
SF2768 binding to Cu(II) results in in situ reduction to Cu(I).
Analogous Cu(II) reduction is also known for the
methanobactins, although the mechanism is not understood
in either case.3−5,31,32 To complement these studies, we carried
out NMR titrations of linear diisonitrile acetate 4, SF2768 (1),
and its unnatural anti-diastereomer (2L,5R)-1, using Cu(I) as
it is diamagnetic. The titration with linear diisonitrile acetate 4
revealed clear shifts of the C3′-proton adjacent to the isonitrile
motif, as well as the diastereotopic C6-protons on the lysinol
chain, with a maximal change at 2:1 ligand-to-copper
stoichiometry (Figure 6). Disappearance of the isonitrile 13C
signal was also observed, consistent with Cu-quadrupole
coupling.25,33 A characteristic IR shift caused by the inductive
effect of the metal34 was observed for the isonitrile group from
2414 to 2184 cm−1.25 Taken together, these results are
consistent with direct Cu binding via the isonitrile motifs of
diisonitrile acetate 4, resulting in conformational changes
throughout the rest of the lysinol backbone. Intepretation of
NMR spectra of the Cu(I) complexes with SF2768 or its
unnatural anti-diastereomer was confounded by multiple
overlapping peaks, as well as significant peak broadening,
possibly arising from the anomeric mixture as well as increased
spectral distinctions between diastereomers at the Cu center.
However, similar downfield shifts of the H3′ resonances were
observed, consistent with similar binding modes.25
Figure 7. (a) UV−vis titration of Cu(4)2 (40 μM) by up to 100
equiv. BCS, indicating no formation of Cu(BCS)2 (λmax = 483 nm).
(b) UV−vis titration of Cu(BCS)2 (40 μM) by diisonitrile acetate 4,
indicating complete competition at 1 equiv.25
treatment of the preformed Cu(BCS)2 complex with
diisonitrile acetate 4 led to a completely linear (hockey stick-
shaped) decrease in absorbance at 483 nm, reaching A = 0
when ∼1 equiv of 4 had been added (Figure 7b).25 Taken
together, these data suggest that the Cu(I) binding affinity of
the diisonitrile acetate 4 is much stronger than that of BCS, but
preclude calculation of that binding affinity because an
equilibrium could not be established. Similar results were
obtained in titrations with SF2768 or its unnatural anti-
diastereomer.25
To investigate further the Cu binding affinity of these
diisonitrile compounds, we attempted competitive UV−vis
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Cellular studies of Zhang and co-workers14 suggest that
corresponding diisonitriles in M. marinum may be involved in
Zn rather than Cu homeostasis. To assess this possibility, we
attempted to form the Zn(II) complex with diisonitrile acetate
4 (1 equiv ZnBr2, 1:1 CH2Cl2/THF).25 Both free diisonitrile 4
and the corresponding 1:1 Zn complex were detected by ESI-
MS analysis, but not the 2:1 Zn complex. Only the free
(3) Kenney, G. E.; Rosenzweig, A. C. Chalkophores. Annu. Rev.
Biochem. 2018, 87, 645−676.
(4) Kenney, G. E.; Rosenzweig, A. C. Methanobactins: Maintaining
copper homeostasis in methanotrophs and beyond. J. Biol. Chem.
2018, 293, 4606−4615.
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Dennison, C.; Vuilleumier, S. Methanobactin and the link between
copper and bacterial methane oxidation. Microbiol. Mol. Biol. Rev.
2016, 80, 387−409.
1
diisonitrile could be readily assigned by H NMR analysis due
to peak broadening. Taken together, these results suggest that
diisonitrile acetate 4 complexes with Zn(II) much more weakly
than with Cu(I). However, because the complete structures of
the M. marinum natural products have not yet been
determined, it is still possible that those compounds may
play a role in Zn homeostasis.
In conclusion, we have developed a modular synthesis of the
diisonitrile natural product SF2768 as well as two acyclic
analogues (3, 4). We have determined that the central lactol
motif of SF2768 has syn stereochemistry, based on comparison
of NMR spectra observed for the corresponding anti-
diastereomer and reported previously for the natural product.
1H NMR titration experiments confirm that diisonitrile acetate
4 binds Cu(I) in a 2:1 ratio and, in conjunction with IR
analysis, are consistent with direct copper binding by the
isonitrile motifs. This work sets the stage for further evaluation
of the physiologic roles of these novel metal chelators.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03348.
Additional figures, materials and methods, synthetic
details, NMR spectra (PDF)
(10) Wang, L.; Zhu, M.; Zhang, Q.; Zhang, X.; Yang, P.; Liu, Z.;
Deng, Y.; Zhu, Y.; Huang, X.; Han, L.; Li, S.; He, J. Diisonitrile
natural product SF2768 functions as a chalkophore that mediates
copper acquisition in Streptomyces thioluteus. ACS Chem. Biol. 2017,
12, 3067−3075.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: tand@mskcc.org.
ORCID
(11) Tabata, Y.; Hatsu, M.; Amano, S.; Shimizu, A.; Imai, S. SF2768,
a new isonitrile antibiotic obtained from Streptomyces. Meiji Seika
Kenkyu Nenpo 1995, 34, 1−9.
(12) Amano, S.-i.; Sakurai, T.; Endo, K.; Takano, H.; Beppu, T.;
Furihata, K.; Sakuda, S.; Ueda, K. A cryptic antibiotic triggered by
monensin. J. Antibiot. 2011, 64, 703.
(13) Sasaki, T.; Watabe, H.; Yoshida, J.; Ito, M.; Shomura, T.;
Sezaki, M. A new antibiotic SF 2369 produced by Actinomadura. Meiji
Seika Kenkyu Nenpo 1987, 10−16.
Derek S. Tan: 0000-0002-7956-9659
Notes
The authors declare no competing financial interest.
(14) Harris, N. C.; Sato, M.; Herman, N. A.; Twigg, F.; Cai, W.; Liu,
J.; Zhu, X.; Downey, J.; Khalaf, R.; Martin, J.; Koshino, H.; Zhang, W.
Biosynthesis of isonitrile lipopeptides by conserved nonribosomal
peptide synthetase gene clusters in Actinobacteria. Proc. Natl. Acad.
Sci. U. S. A. 2017, 114, 7025−7030.
(15) Harris, N. C.; Born, D. A.; Cai, W.; Huang, Y.; Martin, J.;
Khalaf, R.; Drennan, C. L.; Zhang, W. Isonitrile formation by a non-
heme iron(II)-dependent oxidase/decarboxylase. Angew. Chem., Int.
Ed. 2018, 57, 9707−9710.
(16) Adamczyk, M.; Reddy, R. E.; Rege, S. D. Synthesis of
galactosylhydroxylysine and its analogs. Synth. Commun. 2000, 30,
3281−3290.
(17) Friedel, M.; Lindel, T. Synthesis of L-aminohomohistidine (L-
Ahh). Tetrahedron Lett. 2004, 45, 2779−2781.
ACKNOWLEDGMENTS
■
We thank Prof. Michael Glickman and Dr. John Buglino
(MSK) for helpful discussions on chalkophore biosynthesis;
Sho Hagiya and Prof. Kenji Ueda (Nihon University) and Prof.
Shohei Sakuda (Teikyo University) for helpful discussions and
providing NMR spectra of the natural products; Dr. Sheryl
Roberts (MSK) for helpful discussions and assistance with
UV−vis titration experiments; and Dr. George Sukenick and
Rong Wang (MSK Analytical NMR Core Facility) for expert
NMR and mass spectral support. Financial support from the
NIH (CCSG P30 CA008748 to C. B. Thompson) is gratefully
acknowledged.
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(2S,5R)- and (2S,5S)-5-hydroxylysine and of a related α-amino acid
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Tetrahedron: Asymmetry 2004, 15, 2091−2096.
(19) Williams, R. M.; Im, M. N. Asymmetric synthesis of
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